The main types of mental information processing: a systematic structural method

The article describes the main types of mental information processing in the context of a systematic structural method. The author analyses the semantic theories of information. The author reviews the mechanisms of information processing and its qualitative properties. The article describes the mechanism of textual presupposition accommodation

Loss of Sirt1 function improves intestinal anti-bacterial defense and protects from colitis-induced colorectal cancer

Dysfunction of Paneth and goblet cells in the intestine contributes to inflammatory bowel disease (IBD) and colitis-associated colorectal cancer (CAC). Here, we report a role for the NAD+-dependent histone deacetylase SIRT1 in the control of anti-bacterial defense. Mice with an intestinal specific Sirt1 deficiency (Sirt1int-/-) have more Paneth and goblet cells with a consequent rearrangement of the gut microbiota. From a mechanistic point of view, the effects on mouse intestinal cell maturation are mediated by SIRT1-dependent changes in the acetylation status of SPDEF, a master regulator of Paneth and goblet cells. Our results suggest that targeting SIRT1 may be of interest in the management of IBD and CAC

GCN5 maintains muscle integrity by acetylating YY1 to promote dystrophin expression

Protein lysine acetylation is a post-translational modification that regulates protein structure and function. It is targeted to proteins by lysine acetyltransferases (KATs) or removed by lysine deacetylases. This work identifies a role for the KAT enzyme general control of amino acid synthesis protein 5 (GCN5; KAT2A) in regulating muscle integrity by inhibiting DNA binding of the transcription factor/repressor Yin Yang 1 (YY1). Here we report that a muscle-specific mouse knockout of GCN5 (Gcn5(skm)(−/−)) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. GCN5 was found to acetylate YY1 at two residues (K392 and K393), disrupting the interaction between the YY1 zinc finger region and DNA. These findings were supported by human data, including an observed negative correlation between YY1 gene expression and muscle fiber diameter. Collectively, GCN5 positively regulates muscle integrity through maintenance of structural protein expression via acetylation-dependent inhibition of YY1. This work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging

Identification of serine 245 as a novel determinant of the transcriptional regulatory activity of the CREB coactivator CRTC1

Activity-dependent changes in gene expression are implicated in the pathogenesis of Huntington's disease (Gambazzi et al., 2010; Spektor et al., 2002; Luthi-Carter et al., 2000). One of the most important facets of transcriptional dysfunction in HD appears to be the decreased activity-dependent regulation of brain derived neurotrophic factor (BDNF) promoter IV. The CREB coactivator CRTC1 has recently been established to be an important regulator of activity-dependent neuronal gene expression, including the regulation of BDNF (Espana et al., 2010; Zhou et al., 2006). We therefore set out to explore the hypothesis that CRTC1 regulation might be deficient in HD-affected cells. This goal led us to better understand the mechanisms of CRTC1 regulation. We assessed the role of post-translational regulation on the activity of CRTC1 by analogy to another CRTC protein, CRTC2. In the present work, we explored the role of two candidate phosphorylation sites, Ser 151 and Ser 245, in regulating the transcriptional activation mediated by CRTC1 in HEK293T cells and in primary cortical neurons. The involvement of calcineurin in the regulation of CRTC1 activity was established by monitoring CRTC1 intracellular localisation after treatment with cyclosporine A. By mutating serines 151 and 245 to alanines we mimicked the constitutively dephosphorylated state at the candidate positions. We then assessed whether these CRTC1 mutations would show a constitutively active-like behaviour. Expression of CRTC1 constructs in HEK293T cells by transient transfection or in primary neurons via lentiviral gene delivery allowed us to explore whether these serines would affect CRTC1’s intracellular localisation, its activation of gene expression from CRTC1-CREB dependent promoters and its ability to protect neurons from mutant huntigtin-related toxicity. We observed increased nuclear localisation of CRTC1 mutants (S151A, S245A, and S151A+S245A), with the mutation of both serines showing the greatest effect. Whereas S151A showed a significantly induced transcription of CRTC1-CREB target genes, including BDNF, S245A did not produce this effect. Of great interest, however, S245A mutation in combination with S151A produced a significantly greater induction of gene expression than S151A alone. Moreover, the S151A+S245A mutation showed significant neuroprotection in a striatal neuron model of HD. Our observations support the involvement of both Ser151 and Ser245 in the regulation of CRTC1 activity. Taken together with the neuroprotection results, these data also support the novel hypothesis that CRTC1 is a mediator of the HD-related deregulation of neuronal gene expression

Role of ACMSD in regulation of NAD+ metabolism and mitochondrial function

Discovered in the beginning of the 20th century, nicotinamide adenine dinucleotide (NAD+) has evolved from a simple oxidoreductase cofactor to being an essential cosubstrate for a wide range of regulatory proteins that include most notoriously the sirtuin family of NAD+-dependent protein deacylases. Altered NAD+ metabolism is associated with many pathological conditions, including aging and obesity, while beneficial effects of increased NAD+ levels and subsequent sirtuin activation have been established across many different species. Due to their capacity to ameliorate mitochondrial homeostasis, organismal metabolism and lifespan, strategies aiming to boost NAD+ content possess a high therapeutic potential. This thesis describes a novel approach to increase NAD+ levels by stimulating its de novo biosynthesis from the amino acid tryptophan. The enzyme Aminocarboxymuconate Semialdehyde Decarboxylase (ACMSD) converts its substrate, ACMS, into the side branch of the pathway leading to its complete oxidation, consequently limiting the proportion of ACMS capable to generate NAD+. Since reducing ACMSD activity would prevent the flux of metabolites into the side branch and channel them towards NAD+ formation instead, the ultimate goal of this thesis was to establish the role of ACMSD in the control of the intracellular NAD+ content. First, by using genetic tools I found that reduction of ACMSD activity indeed boosts de novo NAD+ synthesis through a mechanism that is conserved from the worm C. elegans to the mouse. Beneficial effects associated with the observed increase in cellular NAD+ levels promoted mitochondrial biogenesis involving sirtuin activation. Secondly, I participated in the development of a panel of potent and selective ACMSD inhibitors. Given the restricted expression of ACMSD in the kidney and liver, its pharmacological inhibition can be a valuable strategy to increase NAD+ content in these tissues and to protect them from injury. After primary characterisation of the ACMSD inhibitors in cell models, I explored the therapeutic potential of the lead compounds to protect from non-alcoholic fatty liver disease and acute kidney injury in mice. Collectively, the data reported in this thesis describe ACMSD as an evolutionary conserved modulator of cellular NAD+ levels, sirtuin activity and mitochondrial homeostasis. Through its impact on cellular NAD+ levels ACMSD inhibition is able to preserve the hepatic and renal function from injury

Modulating NAD(+) metabolism, from bench to bedside

Discovered in the beginning of the 20(th) century, nicotinamide adenine dinucleotide (NAD(+)) has evolved from a simple oxidoreductase cofactor to being an essential cosubstrate for a wide range of regulatory proteins that include the sirtuin family of NAD(+)-dependent protein deacylases, widely recognized regulators of metabolic function and longevity. Altered NAD(+) metabolism is associated with aging and many pathological conditions, such as metabolic diseases and disorders of the muscular and neuronal systems. Conversely, increased NAD(+) levels have shown to be beneficial in a broad spectrum of diseases. Here, we review the fundamental aspects of NAD(+) biochemistry and metabolism and discuss how boosting NAD(+) content can help ameliorate mitochondrial homeostasis and as such improve healthspan and lifespan

The main types of mental information processing: a systematic structural method

The article describes the main types of mental information processing in the context of a systematic structural method. The author analyses the semantic theories of information. The author reviews the mechanisms of information processing and its qualitative properties. The article describes the mechanism of textual presupposition accommodation.El artículo en el marco de un enfoque sistémico-estructural describe las principales direcciones del procesamiento de la información mental. El artículo analiza las teorías semánticas de la información, examina los mecanismos de procesamiento de la información y sus características cualitativas, describe los mecanismos para restaurar la presuposición del texto